PhD (1981), Stanford University
Postdoctoral fellow (1982-1987) Caltech
Research in the Smith group is directed at the development of powerful new technologies, including tools for mass spectrometry proteomics, to drive biological research.
- 1985 Top 100 Innovators, Science Digest
- 1989 Analytical Chemistry Award, Eli Lilly
- 1989 Presidential Young Investigator Award, NSF
- 1994 H.I. Romnes Faculty Fellow, UW-Madison
- 1999 Kellett Mid-Career Research Award, UW-Madison
- 2003 John D. MacArthur Professorship
- 2005 American Chemical Society Award in Chemical Instrumentation
- 2008 Vilas Associate Award, UW-Madison
- 2010 Pittsburgh Analytical Chemistry Award
- 2010 Elected fellow of the American Association for the Advancement of Science
The ability to determine the extent and nature of protein variation is a critical missing piece in proteomics today. A surprise revealed by the success of the human genome project was the much lower than anticipated number of genes present in human, in the range of ~20,000 rather than the predicted ~100,000. This fact has led to the general recognition that much of the complexity and sophistication afforded by our biological machinery is at the level of protein variation rather than just resulting from a large number of distinct genes. These protein variations occur on at least three levels; alternative splicing of the RNA transcript; codon substitutions; and a wide variety of post-translational modifications (PTMs). Determining the identities and abundances of these proteoforms is vital to understanding normal and disease biology. The variations in proteoforms play central roles in a wide variety of biological processes, from cell signaling and signal transduction to gene regulation.
This is a special moment in time. We are in the midst of a technological revolution of unprecedented scope. Next generation sequencing platforms allow rapid, inexpensive and comprehensive transcriptomic analyses, and new mass spectrometers of ever-increasing sensitivity can rapidly determine the accurate mass of intact proteins. This technological convergence opens the possibility of dramatically changing the fundamental paradigm of proteomic analyses. We propose to integrate these state-of-the art genomics and proteomics capabilities into a new two-pronged strategy, in which custom sample-specific proteoform databases will be created and used to identify proteoforms from mass spectrometric data. Employing such an informed database will avoid the combinatorial explosion of possible proteoforms that has severely hindered identification strategies for intact proteins (e.g. top-down proteomics).
Representative Publications (Google Scholar | PUBMED)
Rolfs, Z., Solntsev, S. K., Shortreed, M. R., Frey, B. L. & Smith, L. M. Global Identification of Post-Translationally Spliced Peptides with Neo-Fusion. Journal of proteome research 18, 349-358, doi:10.1021/acs.jproteome.8b00651 (2019).
Spiniello, M. et al. HyPR-MS for Multiplexed Discovery of MALAT1, NEAT1, and NORAD lncRNA Protein Interactomes. Journal of proteome research 17, 3022-3038, doi:10.1021/acs.jproteome.8b00189 (2018).
Schaffer, L. V. et al. Identification and Quantification of Murine Mitochondrial Proteoforms Using an Integrated Top-Down and Intact-Mass Strategy. Journal of proteome research 17, 3526-3536, doi:10.1021/acs.jproteome.8b00469 (2018).
Lu, L. et al. Identification of MS-Cleavable and Noncleavable Chemically Cross-Linked Peptides with MetaMorpheus. Journal of proteome research 17, 2370-2376, doi:10.1021/acs.jproteome.8b00141 (2018).
Cesnik, A. J. et al. Long Noncoding RNAs AC009014.3 and Newly Discovered XPLAID Differentiate Aggressive and Indolent Prostate Cancers. Transl Oncol 11, 808-814, doi:10.1016/j.tranon.2018.04.002 (2018).